Leishmaniasis is a vector-borne Neglected Tropical Disease, caused by protozoan parasites of the genus Leishmania for which there is a shortage of effective and viable non-toxic drugs. There are approximately 1.3 million new cases of leishmaniasis each year with the greatest impact on the poorest communities. This means that desperately needed new antileishmanial treatments have to be both affordable and accessible. Established medicines with cheaper and faster development times may hold the cure for this neglected disease. The repositioning of old drugs for new uses is not a new concept but, with the ambitious target of controlling or eradicating tropical diseases by 2020, this strategy is still an important one. Previous work in our group identified Leishmania major inositol phosphorylceramide synthase (LmjIPCS) as a potential drug target. LmjIPCS is a membrane bound enzyme involved in the biosynthesis of sphingolipids and has a function that differs from its mammalian orthologue (sphingomyelin synthase), potentiating the development of safe, selective antileishmanials. Using a microtiter plate compatible assay, a set of 1040 pharmalogically active compounds were screened for activity against LmjIPCS and parasites. Clemastine, an over-the-counter antihistamine, showed submicromolar potencies against different species of leishmania (L. major, L. amazonensis, L. donovani and L. infantum) and was effective against L. amazonensis intramacrophage amastigotes (EC50 = 0.4 mM). With successful in vitro results and a well-studied pharmacokinetic and mammalian safety profile, clemastine was chosen as an ideal candidate to progress into a mouse model. There was a significant reduction in parasite burden when clemastine was given via the IL route demonstrating its potential as a localised antileishmanial therapy. This presentation will share these findings together with details of synthetic studies towards new active and more accessible analogues.

Repurposing as a strategy for the discovery of a new antileishmanial

256th National Meeting (2018)

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